Type of Document Master's Thesis Author Isin, Emre M. Author's Email Address email@example.com URN etd-11272000-120319 Title
Potential Prodrugs of the Neuronal Nitric Oxide Synthase and Monoamine Oxidase Inhibitor 7-Nitroindazole and Structurally Related Compounds
Degree Master of Science Department Chemistry Advisory Committee
Advisor Name Title Castagnoli, Neal Jr. Committee Chair Dorn, Harry C. Committee Member Kingston, David G. I. Committee Member Tanko, James M. Committee Member Keywords
- organic reaction mechanisms
- tetrahydropyridinyl-based prodrugs
Date of Defense 2000-10-30 Availability unrestricted AbstractParkinson's disease (PD) is a progressive neurodegenerative disorder of unknown cause that afflicts about 1.5 million Americans. The characteristic feature of PD is a deficiency of dopamine in the terminals of nigrostriatal neurons. Two enzyme systems, the neuronal form of nitric oxide synthase (nNOS) and monoamine oxidase B (MAO-B), have been linked to neurodegenerative pathways leading to PD. Several MAO-B and nNOS inhibitors have been evaluated for their neuroprotective properties in the mouse model of neurodegeneration which employs the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). One such compound is 7-nitroindazole (7-NI), a compound which is reported to inhibit both enzymes.
This thesis focuses on the synthesis and biological evaluation of a potential prodrug form of 7-NI and related indazolyl containing compounds which are designed to release the active drugs following a metabolic bioactivation process. These studies have led to a detailed description of the nucleophilic aromatic substitution reactions between 4-chloro-1-methylpyridinium iodide and the indazolyl reactants that were employed as the initial step in the synthesis of the target compounds. The MAO-B substrate and inhibition properties of these "prodrugs" as well as the parent indazolyl compounds were examined. The results are discussed in relation to a previously developed active site model of MAO-B.
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28.8 Modem 56K Modem ISDN (64 Kb) ISDN (128 Kb) Higher-speed Access 1Main.pdf 242.36 Kb 00:01:07 00:00:34 00:00:30 00:00:15 00:00:01 Chapter1-3.pdf 390.20 Kb 00:01:48 00:00:55 00:00:48 00:00:24 00:00:02 Chapter4.pdf 1.47 Mb 00:06:47 00:03:29 00:03:03 00:01:31 00:00:07 Chapter5-7.pdf 551.72 Kb 00:02:33 00:01:18 00:01:08 00:00:34 00:00:02
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